HIV Reports
Revisiting Pneumonia and Exposure Status in Infants Born to HIV-infected Mothers Rasa Izadnegahdar, MPH, MD,* Matthew P. Fox, MPH, DSc,*† Prakash Jeena, MB ChB, FCP,‡ Shamim A. Qazi, MBBS, DCH, MSc, MD,§ and Donald M. Thea, MSc, MD*¶
Abstract: HIV-exposed uninfected infants are an increasing population. Past analyses have often categorized these infants as uninfected leading to inaccurate conclusions. We present a HIV exposure, rather than infection, based reanalysis of treatment failure among children with pneumonia to show that failure odds among HIV-exposed uninfected infants are intermediate between their unexposed and infected counterparts. Additional prospective studies aimed at better understanding this population are needed. Key Words: HIV-exposed uninfected, pneumonia (Pediatr Infect Dis J 2014;33:70–72)
W
ith the successes in implementation of prevention of motherto-child transmission programs and the wide rollout of highly active antiretroviral therapy, infants who are born to HIV-infected mothers but do not go on to develop HIV infection are a rapidly increasing population. Although there remains some persistent risk of postpartum HIV transmission after birth through breast-feeding, perinatal transmission has decreased in some areas to less than 5%.1 This suggests that in many parts of the world, an HIV-exposed uninfected (HEU) infant has already become the most common outcome of pregnancy from an HIV-infected mother. Despite the fact that these children do not develop HIV infection, it is becoming increasingly clear that their immunologic and disease characteristics are not normal. Nonetheless, early studies of the impact of HIV infection on clinical outcomes commonly categorized HIV status into infected and uninfected, prioritizing the child’s infections status over exposure status.
Accepted for publication May 10, 2013. From the *Center for Global Health and Development, Boston University; †Department of Epidemiology, Boston University School of Public Health, Boston, MA; ‡Pediatrics Department, N. Mandela School of Medicine, University of Kwazulu-Natal, Durban, South Africa; §Department of Maternal Newborn Child and Adolescent Health, World Health Organization, Geneva, Switzerland; and ¶Department of International Health, Boston University School of Public Health, Boston, MA. M.P.F. was supported by the National Institute of Allergy and Infectious Diseases (NIAID) under Award Number K01AI083097. The NIAID and USAID had no role in study design, data collection and analysis, decision to publish or preparation of the article. The content is solely the responsibility of the authors and does not necessarily represent the official views of WHO, the NIAID, the National Institutes of Health or other parties. Supported by World Health Organization, USAID and NIAID. S.A.Q. is a medical officer in the Department of Child and Adolescent Health and Development, WHO. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Rasa Izadnegahdar, MPH, MD, Center for Global Health and Development, Boston University, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3301-0070 DOI: 10.1097/INF.0b013e31829f0ade
70 | www.pidj.com
One such study, published by our group in 2006, examined the association of HIV infection with clinical treatment failure among children 2–59 months of age with World Health Organization–defined severe (chest indrawing) pneumonia and without maternal antiretroviral treatment.2 We found that 19% of HIVinfected children but only 10% of HIV-uninfected children met clinical failure criteria by day 2 of therapy. By day 14, failure rates were 32% for HIV-infected children and 21% for HIV-uninfected children. These findings translated to odds ratios for treatment failure among HIV-infected children compared with uninfected children of 2.07 (95% confidence interval: 1.07–4.00) and 1.88 (95% confidence interval: 1.11–3.17) for day 2 and 14, respectively. When we reanalyzed the data by exposure status thereby removing exposed uninfected children from the uninfected category, results were notably different than originally presented. Compared with their infected or unexposed counterparts, HIV-exposed uninfected children were younger and more likely to be hypoxic. They had similar sex distribution and immunization status but had higher average weight for age scores (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/B618). HIV-exposed uninfected children accounted for 33% of treatment failures by day 2 and 20% of treatment failures by day 14 among uninfected children. Although odds ratios as per the original analysis comparing treatment failure between HIV-infected and HIV-uninfected children remained similar, those analyzed by exposure status demonstrated that exposed uninfected children have treatment failure odds that are intermediate between their unexposed and infected counterparts (Table 1). Moreover, the separation of exposed uninfected children into a distinct category unmasked the larger magnitude of treatment failure odds ratios when comparing HIV-infected children to HIV-unexposed children. Other studies have highlighted the importance of assessing the effects of HIV exposure rather than infection and focusing on the unique characteristics of the HIV-exposed uninfected population. These effects can be categorized into 3 distinct categories: 1) clinical presentation, 2) immune dysfunction and 3) vaccination response. Clinically, it is apparent that HIV-exposed uninfected infants have a greater propensity for illness and tend toward more severe disease compared with unexposed children. HEU infants have been shown to have significantly higher than background rates of invasive group B streptococcal infection and bronchiolitis.3,4 The demonstrated increased rate and severity of bronchiolitis infection in this group has been shown to be associated with low maternal and infant CD4 counts. Compared with HIV-unexposed infants, HEU infants have also been shown to have higher rates of hospitalization from all causes in the first year of life, with 50% of the increase attributable to lower respiratory tract infections.5 Differences remained even when controlling for low birthweight, prematurity, missed immunizations, malnutrition and infant anemia. Furthermore, among an age-matched population of HIV-exposed uninfected children undergoing surgery in South Africa, Karpelowsky and colleagues1 have shown higher rates of postsurgical complications, including systemic postoperative
The Pediatric Infectious Disease Journal • Volume 33, Number 1, January 2014
The Pediatric Infectious Disease Journal • Volume 33, Number 1, January 2014
Pneumonia and HIV Status
TABLE 1. Proportions and Odds Ratios of Treatment Failure Among Participants With Known Exposure Status Presented by HIV Infection Status in Original Analysis and by HIV Exposure and Infection Status, Controlling for Age, in Reanalysis
Original analysis HIV-uninfected HIV-infected Reanalysis HIV-unexposed HIV-exposed uninfected HIV-infected
Failure by Day 2
Odds Ratio (95% Confidence Interval)
Failure by Day 14
18/284 (6.3%) 12/82 (14.6%)
Reference 2.53 (1.17–5.51)
45/284 (15.6%) 20/82 (24.4%)
Reference 1.71 (0.94–3.11)
12/244 (4.9%) 6/40 (15.0%) 12/82 (14.6%)
Reference 2.19 (0.75–2.75) 3.48 (1.47–8.22)
36/244 (14.8%) 9/40 (22.5%) 20/82 (24.4%)
Reference 1.18 (0.50–2.75) 1.92 (1.02–3.59)
infection or surgical site complications, when compared with HIV-unexposed children (RR 3.8; 95% confidence interval: 2.1– 7.0). These investigators note that the observed difference may be due to increased malnutrition among HEU children. An exposurebased reanalysis of a large cohort of Kenyan infants recruited from 1992 to 1998 corroborates this by demonstrating frequent rates of growth faltering among HEU infants including 29% as underweight (weight for age Z score
Revisiting Pneumonia and Exposure Status in Infants Born to HIV-infected Mothers Rasa Izadnegahdar, MPH, MD,* Matthew P. Fox, MPH, DSc,*† Prakash Jeena, MB ChB, FCP,‡ Shamim A. Qazi, MBBS, DCH, MSc, MD,§ and Donald M. Thea, MSc, MD*¶
Abstract: HIV-exposed uninfected infants are an increasing population. Past analyses have often categorized these infants as uninfected leading to inaccurate conclusions. We present a HIV exposure, rather than infection, based reanalysis of treatment failure among children with pneumonia to show that failure odds among HIV-exposed uninfected infants are intermediate between their unexposed and infected counterparts. Additional prospective studies aimed at better understanding this population are needed. Key Words: HIV-exposed uninfected, pneumonia (Pediatr Infect Dis J 2014;33:70–72)
W
ith the successes in implementation of prevention of motherto-child transmission programs and the wide rollout of highly active antiretroviral therapy, infants who are born to HIV-infected mothers but do not go on to develop HIV infection are a rapidly increasing population. Although there remains some persistent risk of postpartum HIV transmission after birth through breast-feeding, perinatal transmission has decreased in some areas to less than 5%.1 This suggests that in many parts of the world, an HIV-exposed uninfected (HEU) infant has already become the most common outcome of pregnancy from an HIV-infected mother. Despite the fact that these children do not develop HIV infection, it is becoming increasingly clear that their immunologic and disease characteristics are not normal. Nonetheless, early studies of the impact of HIV infection on clinical outcomes commonly categorized HIV status into infected and uninfected, prioritizing the child’s infections status over exposure status.
Accepted for publication May 10, 2013. From the *Center for Global Health and Development, Boston University; †Department of Epidemiology, Boston University School of Public Health, Boston, MA; ‡Pediatrics Department, N. Mandela School of Medicine, University of Kwazulu-Natal, Durban, South Africa; §Department of Maternal Newborn Child and Adolescent Health, World Health Organization, Geneva, Switzerland; and ¶Department of International Health, Boston University School of Public Health, Boston, MA. M.P.F. was supported by the National Institute of Allergy and Infectious Diseases (NIAID) under Award Number K01AI083097. The NIAID and USAID had no role in study design, data collection and analysis, decision to publish or preparation of the article. The content is solely the responsibility of the authors and does not necessarily represent the official views of WHO, the NIAID, the National Institutes of Health or other parties. Supported by World Health Organization, USAID and NIAID. S.A.Q. is a medical officer in the Department of Child and Adolescent Health and Development, WHO. The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Rasa Izadnegahdar, MPH, MD, Center for Global Health and Development, Boston University, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2013 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3301-0070 DOI: 10.1097/INF.0b013e31829f0ade
70 | www.pidj.com
One such study, published by our group in 2006, examined the association of HIV infection with clinical treatment failure among children 2–59 months of age with World Health Organization–defined severe (chest indrawing) pneumonia and without maternal antiretroviral treatment.2 We found that 19% of HIVinfected children but only 10% of HIV-uninfected children met clinical failure criteria by day 2 of therapy. By day 14, failure rates were 32% for HIV-infected children and 21% for HIV-uninfected children. These findings translated to odds ratios for treatment failure among HIV-infected children compared with uninfected children of 2.07 (95% confidence interval: 1.07–4.00) and 1.88 (95% confidence interval: 1.11–3.17) for day 2 and 14, respectively. When we reanalyzed the data by exposure status thereby removing exposed uninfected children from the uninfected category, results were notably different than originally presented. Compared with their infected or unexposed counterparts, HIV-exposed uninfected children were younger and more likely to be hypoxic. They had similar sex distribution and immunization status but had higher average weight for age scores (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/B618). HIV-exposed uninfected children accounted for 33% of treatment failures by day 2 and 20% of treatment failures by day 14 among uninfected children. Although odds ratios as per the original analysis comparing treatment failure between HIV-infected and HIV-uninfected children remained similar, those analyzed by exposure status demonstrated that exposed uninfected children have treatment failure odds that are intermediate between their unexposed and infected counterparts (Table 1). Moreover, the separation of exposed uninfected children into a distinct category unmasked the larger magnitude of treatment failure odds ratios when comparing HIV-infected children to HIV-unexposed children. Other studies have highlighted the importance of assessing the effects of HIV exposure rather than infection and focusing on the unique characteristics of the HIV-exposed uninfected population. These effects can be categorized into 3 distinct categories: 1) clinical presentation, 2) immune dysfunction and 3) vaccination response. Clinically, it is apparent that HIV-exposed uninfected infants have a greater propensity for illness and tend toward more severe disease compared with unexposed children. HEU infants have been shown to have significantly higher than background rates of invasive group B streptococcal infection and bronchiolitis.3,4 The demonstrated increased rate and severity of bronchiolitis infection in this group has been shown to be associated with low maternal and infant CD4 counts. Compared with HIV-unexposed infants, HEU infants have also been shown to have higher rates of hospitalization from all causes in the first year of life, with 50% of the increase attributable to lower respiratory tract infections.5 Differences remained even when controlling for low birthweight, prematurity, missed immunizations, malnutrition and infant anemia. Furthermore, among an age-matched population of HIV-exposed uninfected children undergoing surgery in South Africa, Karpelowsky and colleagues1 have shown higher rates of postsurgical complications, including systemic postoperative
The Pediatric Infectious Disease Journal • Volume 33, Number 1, January 2014
The Pediatric Infectious Disease Journal • Volume 33, Number 1, January 2014
Pneumonia and HIV Status
TABLE 1. Proportions and Odds Ratios of Treatment Failure Among Participants With Known Exposure Status Presented by HIV Infection Status in Original Analysis and by HIV Exposure and Infection Status, Controlling for Age, in Reanalysis
Original analysis HIV-uninfected HIV-infected Reanalysis HIV-unexposed HIV-exposed uninfected HIV-infected
Failure by Day 2
Odds Ratio (95% Confidence Interval)
Failure by Day 14
18/284 (6.3%) 12/82 (14.6%)
Reference 2.53 (1.17–5.51)
45/284 (15.6%) 20/82 (24.4%)
Reference 1.71 (0.94–3.11)
12/244 (4.9%) 6/40 (15.0%) 12/82 (14.6%)
Reference 2.19 (0.75–2.75) 3.48 (1.47–8.22)
36/244 (14.8%) 9/40 (22.5%) 20/82 (24.4%)
Reference 1.18 (0.50–2.75) 1.92 (1.02–3.59)
infection or surgical site complications, when compared with HIV-unexposed children (RR 3.8; 95% confidence interval: 2.1– 7.0). These investigators note that the observed difference may be due to increased malnutrition among HEU children. An exposurebased reanalysis of a large cohort of Kenyan infants recruited from 1992 to 1998 corroborates this by demonstrating frequent rates of growth faltering among HEU infants including 29% as underweight (weight for age Z score
